1. Field of the Invention
This invention relates generally to the field of inducing nucleation in supersaturated solutions and specifically to the novel process of inducing nucleation in supersaturated solutions using a static electric field to, among other things, to create polymorphs that are unexpected and/or unknown.
2. Prior Art
Crystallization from liquid solution is a ubiquitous phase transition that has great technological importance, but whose mechanism is not well elucidated. It is used to separate and purify industrially important substances such as pharmaceuticals, pigments, dyes and explosives. Nucleation, the initial step in the process of crystallization involving the formation of a critical nucleus, is still poorly understood. There is growing evidence that nucleation from solution is often a two-step process: the formation of a nanoscale, liquid-like solute cluster, followed by an organizational step in which the cluster takes on a crystalline structure.
The process of nucleation is further complicated when the solute under study has the possibility of crystallizing into more than one crystal structure, known as polymorphism. Different polymorphs of a substance may exhibit great differences in chemical and physical properties such as melting point, solubility, dissolution rate, bioavailability and hardness. Living organisms are able to control morphology and polymorphism through biomineralization. The addition of certain impurity chemicals can inhibit or promote the growth of particular crystal surfaces. Such tailor-made additives operate through stereospecific interactions not unlike enzyme-substrate interactions. New polymorphs of organic molecules constitute novel materials that may have important industrial applications. The crystal structure of a material determined by x-ray diffraction gives a complete picture of the arrangement of the atoms (or molecules) of the chemical species in the crystalline state.
The term “polymorphism” is contrasted with “morphology.” Crystals are solids with the atoms, molecules, or ions in a regular repeating structure. The overall external form is referred to as crystal morphology. The term morphology refers to the external shape of the crystal and the planes present, without reference to the internal structure. Crystals obtained experimentally can display different morphology based on different conditions, such as, for example, growth rate, stirring, and the presence of impurities. In contrast, polymorphism refers to the internal alignment and orientation of the molecules. A substance can have several distinct polymorphs and only one morphology, or several distinct morphologies for only one polymorph. Just because the morphology changes does not mean there is a new polymorph, and vice versa. Unlike with different morphologies, one cannot tell by visual observation whether one has a different polymorph.
The prior art produces a substance with a known morphology and crystal structure. It does not produce a substance of unknown crystal structure (a new polymorph) or of unexpected structure (a known polymorph that would not normally occur under these conditions). As discussed above, there is an important distinction between morphology and polymorphism. Morphology is the external appearance of the crystal. In contrast, polymorphism refers to the internal structure of the crystal. It is important to note that crystals of a given substance with different morphologies have the same physical properties (such as melting point, solubility, electrical conductivity, etc) while different polymorphs of the same substance have different properties (e.g., diamond and graphite, which are different polymorphs of carbon).
Polymorphism is quite common in the elements and in inorganic and organic compounds and results in property changes. A dramatic example is carbon, which can crystallize as graphite or as diamond. Diamond is a cubic crystal, whereas graphite is hexagonal. In addition, properties such as hardness, density, shape, vapor pressure, dissolution rate, and electrical conductivity are all quite different for these two solids. These major differences in the properties of two polymorphs are not unique to carbon and can occur in all materials that display polymorphism. Many of the early identifications of polymorphs were minerals, such as calcium carbonate, which has three polymorphs (calcite, aragonite, and vaterite) and zinc sulfide, which has three polymorphs (wurtzite, sphalerite, and matraite). Some well known species have large numbers of polymorphs, for example water, which has eight different solid forms of ice. Organic molecular crystals often have multiple polymorphs that can be of great significance in the pharmaceutical, dye and explosives industries.
Under a given set of conditions, one polymorph is the thermodynamically stable form. This does not mean, however, that other polymorphs cannot exist or form at these conditions, only that one polymorph is stable and other polymorphs present can transform to the stable form. An example of this can be seen in heating (or cooling) a crystalline material with multiple polymorphs. As the temperature changes, the material will eventually enter a region where another polymorph is the stable form. The transformation of one polymorph to another, however, will occur at some rate that may be rapid or very slow. The transformation rate varies because the rate of transition of polymorphs depends on the type of structural changes that are involved.
Transformations can be categorized by the types of structural changes involved, which can roughly be related to the rate of transformation. For example, a transformation in which the lattice network is bent but not broken can be rapid. This type of transformation is known as displacive transformation of secondary coordination. Another type of rapid transformation can involve the breakage of weaker bonds in the crystal structure with the stronger bonds remaining in place. This is then followed by the rotation of parts of the molecule about the structure and the formation of new bonds. This type of transformation is a rotational disorder transformation. Slow transformations usually involve the breakage of the lattice network and major changes in the structure or type of bonding.
Polymorphic transformations also can be classified as first- or second-order transitions. In a first-order transition, the free energies of the two forms become equal at a definite transition temperature, and the physical properties of the crystal undergo significant changes upon transition. In a second-order transition, there is a relatively small change in the crystal lattice, and the two polymorphic forms will be similar. There is no abrupt transition point in a second order transition, although the heat capacity rises to a maximum at a second order transition point.
When a material is crystallized from solution, the transition between polymorphs can occur at a much higher rate because the transition is mediated by the solution phase. Polymorphs of a given material will have different solubilities at a given temperature, with the more stable material having a lower solubility (and a higher melting point) than the less stable polymorph. If two polymorphs are in a saturated solution, the less stable polymorph will dissolve and the more stable polymorph will grow until the transition is complete. The rate of the transition is a function of the difference in the solubility of the two forms and the overall degree of solubility of the compounds in solution. This transition requires that some amount of the stable polymorph be present, meaning that the stable polymorph must nucleate at least one crystal for the transition to begin. If a slurry of solution and crystals of a polymorph stable at a high temperature is cooled to a lower temperature, where another polymorph is the stable phase, the transition of the crystals already present will depend on the presence of nuclei of the new stable phase. The more of these nuclei present, the faster the transition will occur.
It is often possible to crystallize a metastable polymorph by applying a large supersaturation (for example rapid cooling) so that crystals of the metastable form appear before crystals of the stable form. When this occurs, if the solid is removed from the solution rapidly and dried, it is possible to obtain samples of a metastable polymorph that will not easily transform to the stable phase unless heated. If the crystals of the metastable polymorph are left in solution for any length of time, they will likely transform to the stable form by going through the solution phase. If seeds of the stable polymorph are added to the solution, the transition will occur more rapidly. At first-order phase-transition temperatures, the solubility of the two forms will be equal and both can exist.
When a material that displays polymorphism is crystallized, a metastable phase often appears first and then transforms into a stable form. This observation is summarized by Ostwald's step rule, which is also known as the Law of Successive Reactions. This law states that, in any process, the state that is initially obtained is not the most stable state but the least stable state that is closest, in terms of free-energy change, to the original state. In a crystallization process, therefore, it is possible to envision the phase transformation first occurring into the least stable polymorph (or even an amorphous phase), which transforms through a series of stages to successively more stable forms until the equilibrium form is obtained. While Ostwald's law has been observed in a wide variety of systems, it is most likely to be seen in organic molecular crystals.
Another interesting feature of organic molecular crystals is that the molecular conformation of a species can be different in two polymorphs of the same material. By molecular conformation, we are referring to the shape of the molecule. The same molecule can display different shapes (conformations by rotations about single bonds for example. Conformational polymorphism is the existence of polymorphs of the same substance in which the molecules present are in different conformations.
It is known that by subjecting some supersaturated solutions to laser light, the onset of nucleation occurs. Prior to nucleation, the supersaturated solution contains “clusters” of molecules that are not arranged in the lattice structure of a crystal. The oscillating optical electric field of the laser light helps to align or organize the molecules in the clusters, through the optical Kerr effect, into a lattice arrangement resulting in the formation of nuclei and, after time, crystals. Garetz, B. A. et al., Nonphotochemical, Polarization-Dependent, Laser-Induced Nucleation in Supersaturated Aqueous Urea Solutions, Physical Review Letters, Vol. 77, No. 16, pp. 3475-6 (1996). In this study, we accidentally discovered that intense nanosecond near-infrared laser pulses could induce supersaturated aqueous urea solutions to nucleate. We called this phenomenon non-photochemical laser-induced nucleation (NPLIN) to distinguish it from the better-known, century-old field of ultraviolet and visible light-induced nucleation in supersaturated vapors, the mechanism of which typically involves the photochemical generation of a nonvolatile product that acts as a nucleus for the growth of the condensed phase.
We also have shown that supersaturated aqueous glycine 4.5 to 4.8 molal (3.7 to 3.9 M) could be induced to crystallize into either the α or γ polymorph depending on the polarization state of the laser beam. Garetz, B. A. et al., Physical Review Letters, Vol. 89, No. 14, pp. 175501 (2002). Spontaneous nucleation at these concentrations always produces α glycine, although γ glycine is the most stable polymorph. We attributed both the urea and glycine observations to the interaction of preexisting large solute clusters with the intense electric field of the light, causing an organization of the cluster through the electric field-induced alignment of molecules (i.e. the optical Kerr effect) in the cluster. Linear and circular polarizations induce different types of alignment and thus induce the nucleation of different polymorphs. This “polarization switching” is the strongest evidence to date that the mechanism for NPLIN is not photochemical.
The present invention concerns the novel application of a static (DC) electric field to a supersaturated solution, rather than the application of an oscillating optical electric field that was the subject of the Garetz, et al. paper discussed above and the previous laser-related patent by Myerson and Garetz, U.S. Pat. No. 6,426,406, and the unexpected result that a static (DC) electric field will induce nucleation in the supersaturated solution.